- Email: [email protected]
Chemotherapy for advanced hormone refractory prostate cancer
CHEMOTHERAPY FOR ADVANCED HORMONE REFRACTORY PROSTATE CANCER DANIEL P. PETRYLAK, M.D.
ABSTRACT Men with metastatic prostate cancer treated with androgen ablation respond rapidly and often dramatically to therapy, with improvement of bone pain, regression of soft tissue metastases, and declines in serum prostate-specific antigen (PSA). Unfortunately, few treatment options are available to men who progress after hormone therapy. Recent studies in the mechanism of anticancer drug action have focused on the proteins that regulate apoptosis or programmed cell death as a target for the treatment of hormoneresistant prostate cancer. New treatments are now being designed with both resistance and apoptotic pathways in mind. US Food and Drug Administration (FDA) approval of the combination of mitoxantrone and prednisone for the palliation of bone pain in men with hormone refractory prostate cancer demonstrates that chemotherapy can be effective. Two randomized trials have demonstrated the superiority of mitoxantrone combined with a corticosteroid over corticosteroid therapy in alleviating bone pain. The combination of estramustine with vinblastine, or VP-16, is commonly used in clinical practice with both regimens demonstrating significant PSA declines. When estramustine is combined with either paclitaxel or docetaxel in vitro, greater than additive in vitro cytotoxicity is noted. Phase I and II studies of taxane-based therapy in hormone refractory prostate cancer demonstrate improved survival when compared with historical controls, but phase III studies are necessary to confirm these preliminary observations. UROLOGY 54 (Suppl 6A): 30–35, 1999. © 1999, Elsevier Science Inc.
M
en with metastatic prostate cancer treated with androgen ablation respond rapidly and often dramatically to therapy, with improvement of bone pain, regression of soft tissue metastases, and decreases in serum prostate-specific antigen (PSA). Unfortunately, androgen ablation is not curative; the duration of response is often short (median, 12 to 18 months), with almost all patients succumbing to their disease. The median survival of patients with hormone refractory prostate cancer is approximately 9 to 12 months; an estimated 37,000 men will die from metastatic hormone refractory prostate cancer in the United States in 1999.1 Traditionally, physicians have had few options for treating hormone refractory prostate cancer because From the Genitourinary Oncology Program, Division of Medical Oncology, Columbia Presbyterian Medical Center, New York, New York The author is a study investigator for Rhoˆne-Poulenc Rorer and Pharmacia Upjohn Reprint requests: Daniel P. Petrylak, MD, Genitourinary Oncology Program, Division of Medical Oncology, Columbia Presbyterian Medical Center, 161 Fort Washington Avenue, New York, NY 10032
30
© 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
chemotherapy was perceived to be ineffective. A review by Yagoda and Petrylak2 of 26 studies performed between 1988 and 1991 demonstrated a disappointing overall response rate of only 8.7% (95% confidence intervals ⫽ 6.4% to 9.0%), without a trend toward improvement in survival. Over the past 5 years, new and more effective treatments have been developed based on an increased understanding of the biology of this form of prostate cancer. The therapeutic targets that have emerged include the proteins that both negatively and positively modulate apoptosis, cytoplasmic microtubules, the nuclear matrix, peptide growth factors, and topoisomerases. The recent approval of the mitoxantrone/prednisone combination for the palliation of bone pain in patients with hormone refractory prostate cancer has helped dispel the concept that chemotherapy is ineffective. Along with other new and promising agents and therapies, oncologists have more options for treating hormone refractory prostate cancer, which, at the very least, can improve quality of life and may even prove to prolong survival. This article will review some of these treatment combinations. 0090-4295/99/$20.00 PII S0090-4295(99)00452-5
MECHANISMS OF CHEMOTHERAPEUTIC CELL DEATH Classic drug resistance mechanisms (e.g., multidrug resistance through p-glycoprotein, as well as alterations of the enzyme pathways responsible for antimetabolite activity) are only partially responsible for the ineffectiveness of some chemotherapeutic agents. Recent studies in the mechanism of anticancer drug action have focused on the proteins that regulate apoptosis or programmed cell death, which can be induced by growth factor deprivation, glucocorticoids, and chemotherapy. New treatments are now being designed with both resistance and apoptotic pathways in mind. In designing rational combinations, the oncologist should now account for complementary cell death mechanisms and potential resistance mechanisms. Several different pro- and anti-apoptotic pathways exist and have been identified in androgen-independent prostate cancer cell lines and tissues. The antiapoptotic protein bcl-2 is expressed in approximately 65% of androgen-independent human prostate cancer specimens.3 Transfection of bcl-2 into the human prostate cancer cell line LNCaP imparts resistance to androgen deprivation.4 Bcl-2 transfection into the Dunning-G rat prostate cancer cell line will significantly decrease the cytotoxic effect of doxorubicin when compared with nontransfected lines.5 Thus, bcl-2 may impart both androgen-independent growth as well as chemoresistance. Chemotherapeutic agents, which inactivate bcl-2 by phosphorylation, include those that stabilize and destabilize tubulin, such as the taxanes and vinca alkaloids. The Fas (AP0-1, CD95) ligand, the target of which is a cell surface protein receptor, is expressed in human prostate cancer cell lines that are sensitive to anti-Fas mediated cytotoxic apoptosis.6 Modulation of these pathways may overcome an apoptotic block rendered by mutant p53, which as wild type is necessary for some forms of chemotherapy-induced apoptosis. Mutant p53 is expressed in approximately 80% of human androgenindependent prostate bone marrow metastates in patients who failed androgen ablation.7 RESPONSE ASSESSMENT Assessment of anticancer drug activity in patients with hormone refractory prostate cancer has presented a challenge to oncologists over the past 10 years. Because approximately 80% of patients have disease limited to bone, standard phase II criteria cannot be used for the measurement of response. Surrogate endpoints are currently used in the reporting of clinical trials. These include post therapy decreases in serum PSA, quality of life, and pain scales. A decrease in PSA appears to correlate with survival. UROLOGY 54 (Supplement 6A), December 1999
One of the most controversial surrogate markers is the decrease in serum PSA as a response parameter. Studies have indicated that decreases in this marker can be prognostic. A mulitvariate analysis by Kelly et al.,8 of 110 patients treated in seven consecutive hormone refractory prostate cancer clinical trials at Memorial Sloan Kettering Cancer Center, demonstrated that PSA decreases of ⱖ 50% and a decrease in the natural log of lactic dehydrogenase (LDH) were the most important prognostic factors for survival. A second analysis by Smith et al.9 found that a PSA ⱖ 50% 8 weeks post-treatment in patients treated with estramustine and etoposide was predictive of prolonged survival. Caution must be exercised when interpreting PSA data, as some chemotherapeutic agents may modulate PSA expression.10 Suramin, the putative growth factor antagonist, has been demonstrated to decrease expression of PSA messenger RNA without causing cell death. Retinoids may actually increase PSA expression and, thus, can mislead the investigator to believe that a drug is inactive in a patient. Although PSA can serve as a preliminary screen for drug activity, the efficacy of chemotherapeutic drugs must ultimately be assessed in randomized phase III trials. MITOXANTRONE-BASED REGIMENS Initial phase II studies using mitoxantrone, a topoisomerase II inhibitor, and 10 mg prednisone given orally twice a day demonstrated that 36% of the men treated had a palliative response; 1 of 7 patients with measurable disease evidenced a partial response.11 Two randomized trials have demonstrated the superiority of this combination over corticosteroid therapy in alleviating bone pain. Tannock et al. randomized 161 men with hormone refractory prostate cancer to receive either one dose of 10 mg prednisone, or 12 mg/m2 mitoxantrone every 3 weeks combined with prednisone. A significant improvement in palliation of bone pain (29% vs. 10%, P ⫽ 0.011) was observed in patients who received the combination when compared with those who only received prednisone. The duration of this pain response in patients treated with the combination was also significantly longer (43 vs. 18 weeks, P ⬍ 0.0001). Of the 50 patients who initially received prednisone and failed, 22% responded, as evidenced by improvement of bone pain, to the addition of mitoxantrone. This cross-over design precluded the detection of a survival difference.12 A Cancer and Leukemia Group B (CALGB) study compared the combination of 40 mg hydrocortisone with 14 mg/m2 mitoxantrone every 3 weeks to 40 mg cortisone. The entry criteria and endpoints for this trial differed significantly from those of the Canadian study; asymptomatic patients were eligi31
ble. The primary endpoint of this trial was survival, with palliation of bone pain included in the secondary endpoints. No difference in survival was seen between the two arms, with patients surviving a median of 12.6 and 12.3 months for hydrocortisone and the combination of mitoxantrone and hydrocortisone, respectively. Time to treatment failure and disease progression were improved by 1.4 months when patients were treated with mitoxantrone combined with hydrocortisone. Quality of life indexes were better in the combination therapy arm, particularly for pain control.13 Based on the data from these two phase III studies, mitoxantrone was approved by the Food and Drug Administration for palliation of symptomatic bone pain in men with hormone refractory prostate cancer. ESTRAMUSTINE-BASED REGIMENS Estramustine, a combination of an estrogen with a nor-nitrogen mustard, disrupts cytoplasmic microtubules, inhibits assembly of the nuclear matrix, and inhibits the multidrug resistance transporter p-glycoprotein.14 The combination of estramustine with vinblastine,15–17 or VP-16,18 is commonly used in clinical practice with both regimens demonstrating a decrease in PSA of ⱖ50% in 45% to 52% of patients, and objective responses in 26% to 33% of patients (Table I). A recent study randomized 201 patients to receive either the combination of 600 mg/m2 estramustine given orally plus 4 mg/m2 vinblastine given intravenously once a week for 6 weeks or 4 mg/m2 vinblastine alone given intravenously for 6 weeks. Treatment in each arm was repeated after a 2-week break. The results demonstrated a trend toward improved survival in the estramustine/vinblastine arm (11.9 vs 9.2 months for vinblastine alone) and a small, yet statistically significant, improvement in time to progression for the combination therapy arm. Estramustine may provide myeloprotection; those patients who received the combination of estramustine plus vinblastine had a significantly lower rate of granulocytopenia (grades 2, 3, and 4 ⫽ 7%, 7%, and 1%) when compared with those who received vinblastine alone (grades 2, 3, and 4 ⫽ 27%, 18%, and 9%).19 TAXANE-BASED THERAPY Taxanes, either as single agents or combined with estramustine, have been evaluated extensively in hormone refractory prostate cancer. Differences in chemical structure may account for different sites of action of the taxanes. Preclinical studies demonstrate that docetaxel and paclitaxel bind to different sites on B tubulin (Tau vs. Nterminal), affect different mitotic structures (cen32
trosome vs. mitotic spindle), and arrest cells at different phases of the cell cycle (S vs. G2M).20 Although the mechanism of the antitumor activity of the taxanes is postulated to be a result of the inhibition of depolymerization of microtubules, recent data also demonstrate that both docetaxel and paclitaxel inhibit the anti-apoptotic effect of bcl-2. In vitro, docetaxel is approximately 100-fold more effective in phosphorylating bcl-2 than paclitaxel.21 This may account for the observed differences in clinical activity between these drugs as single agents in men with hormone refractory prostate cancer. Initial studies using paclitaxel, as a single agent at doses of 130 mg/m2 to 170 mg/m2 by continuous infusion over 24 hours, demonstrated a partial response rate of 4.3%, with one patient having a ⬎75% decrease in PSA.22 In contrast, when patients are treated with 75 mg/m2 docetaxel every 3 weeks, 62% of patients demonstrated a greater than 50% decrease in PSA, with 28% having a partial response in soft tissue metastases.23 However, one cannot make any definite conclusions about the efficacy of a particular taxane based on these small Phase II studies. When estramustine is combined with either paclitaxel or docetaxel in vitro, greater than additive cytotoxicity is noted.24 Hudes et al.25 evaluated the combination of 120 mg/m2 estramustine plus paclitaxel by continuous infusion over 96 hours in 33 evaluable hormone refractory prostate cancer patients and found that 52% of patients treated had a ⬎50% PSA decline. Objective responses were observed in 44% of patients with measurable soft tissue lesions. The median survival reported in this study was 17 months. This regimen was well tolerated, with the most common grade 3 or 4 side effects being leukopenia (21.2%) and anemia (18.1%). Grade 3 or 4 toxicities attributed to estramustine included edema (15.2%), nausea (6.1%), and vascular events (6.1%). In a phase I study, Petrylak et al.26 combined 280 mg estramustine three times a day for the first 5 days with 40 mg/m2 to 80 mg/m2 docetaxel (day 2) every 21 days in 34 men with hormone refractory prostate cancer. Overall, 62% of patients treated with docetaxel had a ⱖ50% PSA decrease; objective responses were observed in 28% of patients (Table II). Of 15 patients with symptomatic bone pain requiring narcotic analgesia, 53% discontinued all pain medications for a median of 6 weeks. Neutropenia was dose-limiting at 80 mg/m2. The recommended phase II dose of estramustine and docetaxel was 70 mg/m2 in minimally pretreated patients (MPT) (minimal pretreatment: ⱕ2 prior chemotherapies, ⱕ2 prior radiation therapies, no history of radioisotope therapy, no evidence of superscan on bone scan, and no history of whole pelvic radiation therUROLOGY 54 (Supplement 6A), December 1999
TABLE I. Estramustine-based chemotherapy trials in androgenindependent prostate cancer Drug/Combination Estramustine Estramustine Estramustine Estramustine
⫹ ⫹ ⫹ ⫹
vinblastine etoposide paclitaxel docetaxel
N
PSA Decrease >50%
Objective Response
83 42 34 34
45% 52% 52% 62%
26% 33% 44% 28%
PSA ⫽ prostate-specific antigen.
TABLE II. Docetaxel ⴙ estramustine: phase I studies PSA Study Petrylak et al.26 MPT EPT Kreis et al.27 Natale et al.32 (E ⫹ T)
Patients
>50%
>75%
20 12 17 13
70% 50% 82% 77%
40% 8% 67% 46%
Objective Response*
Symptomatic Improvement
Median Survival
28%
53%
24 mo
NR 60%
NR 77%
NR NR
Recommended Phase II Regimen (mg/m2) T T T T
70 60 70 35
3 3 3 1
times/week; E 280 times/wk; E 280 times/wk; E 12/kg/day time/wk; E 280–420
E ⫽ estramustine; EPT ⫽ extensively pretreated patients; MPT ⫽ minimally pretreated patients; NR ⫽ no response; PSA ⫽ prostate-specific antigen; T ⫽ docetaxel.
apy), and 60 mg/m2 in patients who had extensive prior therapy (EPT) (extensively pretreated patients who did not fit the MPT category). A second phase I study by Kreis et al.27 evaluated the combination of 14 mg/kg/day estramustine continuously with 40 mg/m2 to 70 mg/m2 docetaxel. Neutropenia was dose-limiting at 80 mg/ m2. In 17 patients treated at dosages ranging from 40 mg/m2 to 70 mg/m2, 82% of patients achieved a ⬎50% decrease in PSA. Phase II studies have confirmed this initial PSA decrease rate. In a study designed to evaluate the independent response rate of 60 mg dexamethaseone given orally every 3 weeks, 0 of 12 patients had a 50% PSA decrease, whereas 11 of 12 patients treated with 70 mg/m2 estramustine had a ⬎50% PSA decrease; 3 of 4 patients had a partial response in soft tissue.28 Savarese et al.29 evaluated 10 mg/kg estramustine given in the first 5 days with 70 mg/m2 docetaxel and 40 mg hydrocortisone given once orally in 40 men with hormone refractory prostate cancer. Of 9 patients with soft-tissue metastases, 4 had a partial response. A ⬎50% PSA decrease was observed in 11 of 19 evaluable patients. Although neutropenia appears to be the most common side effect with this combination, the most serious side effects of venous or arterial vascular events occurred in 10% of patients treated with the estramustine/docetaxel combination. It may be possible to reduce the rate of thromboembolic events by either reducing the estramustine dose or adding prophylactic anticoagulants. UROLOGY 54 (Supplement 6A), December 1999
Taxanes, administered weekly, are also being evaluated in men with hormone refractory prostate cancer.30 Using a continuous oral dosage of 600 mg/m2/day estramustine starting 24 hours before paclitaxel and 60 mg/m2 to 118 mg/m2 paclitaxel every week, Haas et al.31 found the dosage of estramustine had to be reduced to 280 mg twice a day because of nausea or thromboembolism. Six of 11 patients with measurable disease had a partial response, whereas 9 of 14 patients had a ⬎50% PSA decrease. Natale and Zaretsky32 studied 20 mg/m2 to 40 mg/m2 docetaxel given weekly with 420 mg estramustine administered for 3 or 4 days. Deep venous thrombosis or grade 3/4 neutropenia was observed in 2 and 4 patients, respectively. Of the 18 patients entered, 78% and 67% of patients had a ⬎50% PSA decrease or objective response, respectively. PHASE III SOUTHWEST ONCOLOGY GROUP STUDY In 1999, patients with hormone refractory prostate cancer are being treated earlier; in fact, a greater proportion of men are classified as hormone refractory based solely on an increasing PSA, without progression by bone scan or computerized tomography. Although the reported estramustine/ docetaxel studies required patients to have radiographic evidence for metastases, it is possible that increases in survival could be related to patient selection or a statistical variance based on the small numbers of patients treated. Only a randomized 33
TABLE III. Southwest Oncology Group (SWOG) 9916: A randomized phase III study of docetaxel ⴙ estramustine versus mitoxantrone ⴙ prednisone in patients with hormone refractory prostate cancer* Hormone Refractory Advanced Prostate Cancer
R A ------⬎ N D O M I Z ------⬎ E
Docetaxel 60 mg/m2 day 2† ⫹ estramustine 280 mg tid days 1–5 q3 wk
Mitoxantrone‡ 12 mg/m2 day 1 ⫹ prednisone 5 mg bid days 1–21 q3 wk
* 620 patients to be entered to detect a 33% survival difference. † Escalated to 70 mg/m2 if no grade 3 or 4 toxicities are observed in cycle 1. Dexamethasone was given at midnight, 6 AM, and just prior to docetaxel administration. ‡ Escalated to 14 mg/m2 if no grade 3 or 4 toxicities are observed in cycle 1.
study would definitively answer the question of whether estramustine/docetaxel truly improves survival in this patient population. In 1999, a phase III study will begin in the Southwest Oncology Group to evaluate survival in patients with metastatic hormone refractory prostate cancer (Table III). The control arm is 12 mg/m2 mitoxantrone (escalated to 14 mg/m2 if no grade 3 or 4 toxicities are observed in cycle 1) combined with 5 mg prednisone given orally twice a day, days 1–21 q3 weeks. In arm 2, patients will be treated with 280 mg estramustine given orally three times a day for days 1 to 5, 60 mg/m2 docetaxel on day 2 (escalated to 70 mg/m2 if no grade 3 or 4 toxicities are observed in cycle 1), and 20 mg dexamethasone given at midnight, 6 AM, and just before docetaxel administration. The trial is designed to detect a 33% difference in survival between the two arms at a power of 80%. Secondary endpoints include quality of life, response in measurable disease, and improvement of bone pain. The trial will accrue 620 patients over a 3-year period. CONCLUSION To date, no single agent or combination therapy has proven to prolong survival in patients with metastatic hormone-refractory prostate cancer. Taxanes, administered singly or in combination with estramustine, have demonstrated activity in early phase I/II studies in patients with hormone refractory prostate cancer. A trend toward improved survival has been observed in phase I studies combining estramustine and docetaxel, as well as in phase II studies of estramustine and paclitaxel. These results in small cohorts of patients have provided impetus for future randomized studies. Only randomized trials can confirm whether these survival trends can be confirmed or were the result of patient selection or statistical 34
variation. Other studies are needed to determine the most active and tolerable taxane schedule (weekly vs. every 3 weeks), the optimal dosage of estramustine, or if estramustine is even necessary. REFERENCES 1. Landis SH, Murray T, Boldin S, and Wingo PA. Cancer statistics, 1999. CA 49: 8 –32, 1999. 2. Yagoda A, and Petrylak D: Cytotoxic chemotherapy for advanced hormone resistant prostate cancer. Cancer 71: 1098 –1109, 1993. 3. McDonnel TJ, Navone NM, Troncoso P, et al.: Expression of bcl-2 oncoprotein and p53 protein accumulation in bone marrow metastases of androgen independent prostate cancer. J Urol 157: 569 –574, 1997. 4. Raffo AJ, Perlman H, Chen MW, Day ML, Streitman, JS, and Buttyan R: Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res 55: 4438 – 4445, 1995. 5. Tu SM, McConnel K, Marin MC, Campbell ML, Fernandez A, von Eschenbach AC, and McDonnell TJ: Combination adriamycin and suramin induces apoptosis in bcl-2 expressing prostate carcinoma cells. Cancer Lett 13: 147–155, 1995. 6. Uslu R, Borsellino N, Frost T, et al.: Chemosensitization of human prostate carcinoma cell lines to anti-Fas-mediated cytotoxicity and apoptosis. Clin Cancer Res 3: 963–972, 1997. 7. Meyers FJ, Gumerlock PH, Chi SG, Borchers H, Deitch AD, and deVere White RW: Very frequent p53 mutations in metastatic prostate carcinoma and in matched primary tumors. Cancer 15: 2534 –2539, 1998. 8. Kelly WK, Scher HI, Mazumadar M, et al.: Prostatespecific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol 11: 607– 615, 1993. 9. Smith DC, Dunn RL, Strawderman MS, and Pienta KJ: Change in serum prostate-specific antigen as a marker of response to cytotoxic therapy for hormone-refractory prostate cancer. J Clin Oncol 16: 1835–1843, 1998. 10. Thalmann GN, Sikes RA, Chang S, et al.: Suramin-induced decrease in prostate-specific antigen expression with no effect on tumor growth in the LNCaP model of human prostate cancer. J Natl Cancer Institute 88: 794 – 802, 1996. 11. Moore MJ, Osoba D, Murphy K, Tannock IF, Armitage A, Findlay B, Coppin C, Neville A, Venner P, Wilson J: Use of palliative end points to evaluate the effects of mitoxantrone UROLOGY 54 (Supplement 6A), December 1999
and low-dose prednisone in patients with hormonally resistant prostate cancer. J Clin Oncol 12: 689 – 694, 1994. 12. Tannock IF, Osoba D, Stockler MR, et al.: Chemotherapy with mitoxantrone plus prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial symptomatic hormone-resistant prostate cancer: a Canadian randomized trial palliative end points. J Clin Oncol 14: 1756 –1764, 1996. 13. Kantoff PW, Halabi S, Conaway M, et al.: Hydrocortisone with or without mitoxantrone in men with hormonerefractory prostate cancer: results of the Cancer and Leukemia Group B 9182 Study. J Clin Oncol 17: 2506 –2513, 1999. 14. Perry CA, and McTavish D: Estramustine phosphate sodium. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs and Aging 7: 149 –174, 1995. 15. Seidman AD, Scher HI, Petrylak D, Dershaw DD, and Curley T: Estramustine and vinblastine: use of prostate specific antigen as a clinical trial end point in hormone refractory prostate cancer. J Urol 147: 931–934, 1992. 16. Amato RJ, Ellenhorst J, Bui C, and Logothetis CJ: Estramustine and vinblastine for patients with androgen-independent adenocarcinoma of the prostate. Urol Oncol 2: 168 – 172, 1995. 17. Hudes GH, Greenberg R, Krigel R, et al.: Phase II study of estramustine and vinblastine, two microtubule inhibitors in hormone refractory prostate cancer. J Clin Oncol 10: 154 – 1761, 1992. 18. Pienta KJ, Redman B, Hussain M, et al.: Phase II evaluation of oral estramustine and oral etoposide in hormonerefractory adenocarcinoma of the prostate. J Clin Oncol 12: 2005–2012, 1994. 19. Hudes G, Einhorn L, Ross E, et al.: Vinblastine vs. vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: a Hoosier Oncology Group and Fox Chase Network Phase III trial. J Clin Oncol 17: 3160 –3166, 1999. 20. Lavelle F, Bissery MC, Combeau C, Riou JF, Vrignaud P, and Andre S: Preclinical evaluation of docetaxel (taxotere). Semin Oncol 22 (2 Suppl 4): 3–16, 1995. 21. Haldar S, Basu A, and Croce C: Bcl-2 is the guardian of microtubule integrity. Canc Res 57: 229 –233, 1997. 22. Roth BJ, Yeap BY, Wilding G, et al.: Taxol in advanced hormone-refractory prostate carcinoma phase II trial of the
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eastern cooperative oncology group. Cancer 72: 2457–2460, 1993. 23. Schultz M, Wei J, Picus J, and Cochran J: A phase II trial of docetaxel in patients with hormone refractory prostate cancer (HRPC) (abst). Proc Am Soc Clin Oncol 18: 355a, 1999. 24. Kreis W, Budman DR, and Calabro A: Unique synergism or antagonism of combinations of chemotherapeutic and hormonal agents in human prostate cancer cell lines. Br J Urol 79: 196 –202, 1997. 25. Hudes GR, Nathan F, Khater C, et al.: Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 15: 3156 –3163, 1997. 26. Petrylak DP, Macarthur RB, O’Connor J, Shelton G, Judge T, Balog J, Pfaff C, Bagiella E, Heitjan D, Fine R, et al.: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17: 958 –967, 1999. 27. Kreis W, Budman DR, Fetten J, Gonzales AL, Barile B, and Vinciguerra V: Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone refractory prostate carcinoma. Ann Oncol 10: 33–38, 1999. 28. Sheton G, Gerson H, Zuech N, et al.: Activity of docetaxel (D) ⫹ estramustine (E) after dexamethasone (Dex) treatment in patients (pts) with androgen-insensitive prostate cancer (abst). Proc Am Soc Clin Oncol 17: 343a, 22, 1998. 29. Savarese DM, Taplin ME, Marchesani B, et al.: A phase II study of docetaxel, estramustine, and low dose hydrocortisone in hormone refractory prostate cancer: CALGB 9780 (abst). Proc Am Soc Clin Oncol 18: 321a, 1999. 30. Sinibaldi VJ, Carducci MA, and Moore-Cooper S: A phase II study evaluating a one day course of estramustine phosphate (EMP) and docetaxel (D) in patients (pts) with hormone refractory prostate cancer (HRPC) (abst). Proc Am Soc Clin Oncol 18: 322a, 1999. 31. Haas N, Garay C, Roth B, et al.: Weekly paclitaxel by 3 hour infusion plus oral estramustine (EMP) in metastatic hormone-refractory prostate cancer (HRPC) (abst). Proc Am Soc Clin Oncol 18: 340a, 1999. 32. Natale RB, and Zaretsky S: Phase I/II study of estramustine (E) and taxotere(T) in patients with metastatic hormonerefractory prostate cancer (HRPC) (abst). Proc Am Soc Clin Oncol 17: 348a, 1998.
35
ABSTRACT Men with metastatic prostate cancer treated with androgen ablation respond rapidly and often dramatically to therapy, with improvement of bone pain, regression of soft tissue metastases, and declines in serum prostate-specific antigen (PSA). Unfortunately, few treatment options are available to men who progress after hormone therapy. Recent studies in the mechanism of anticancer drug action have focused on the proteins that regulate apoptosis or programmed cell death as a target for the treatment of hormoneresistant prostate cancer. New treatments are now being designed with both resistance and apoptotic pathways in mind. US Food and Drug Administration (FDA) approval of the combination of mitoxantrone and prednisone for the palliation of bone pain in men with hormone refractory prostate cancer demonstrates that chemotherapy can be effective. Two randomized trials have demonstrated the superiority of mitoxantrone combined with a corticosteroid over corticosteroid therapy in alleviating bone pain. The combination of estramustine with vinblastine, or VP-16, is commonly used in clinical practice with both regimens demonstrating significant PSA declines. When estramustine is combined with either paclitaxel or docetaxel in vitro, greater than additive in vitro cytotoxicity is noted. Phase I and II studies of taxane-based therapy in hormone refractory prostate cancer demonstrate improved survival when compared with historical controls, but phase III studies are necessary to confirm these preliminary observations. UROLOGY 54 (Suppl 6A): 30–35, 1999. © 1999, Elsevier Science Inc.
M
en with metastatic prostate cancer treated with androgen ablation respond rapidly and often dramatically to therapy, with improvement of bone pain, regression of soft tissue metastases, and decreases in serum prostate-specific antigen (PSA). Unfortunately, androgen ablation is not curative; the duration of response is often short (median, 12 to 18 months), with almost all patients succumbing to their disease. The median survival of patients with hormone refractory prostate cancer is approximately 9 to 12 months; an estimated 37,000 men will die from metastatic hormone refractory prostate cancer in the United States in 1999.1 Traditionally, physicians have had few options for treating hormone refractory prostate cancer because From the Genitourinary Oncology Program, Division of Medical Oncology, Columbia Presbyterian Medical Center, New York, New York The author is a study investigator for Rhoˆne-Poulenc Rorer and Pharmacia Upjohn Reprint requests: Daniel P. Petrylak, MD, Genitourinary Oncology Program, Division of Medical Oncology, Columbia Presbyterian Medical Center, 161 Fort Washington Avenue, New York, NY 10032
30
© 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
chemotherapy was perceived to be ineffective. A review by Yagoda and Petrylak2 of 26 studies performed between 1988 and 1991 demonstrated a disappointing overall response rate of only 8.7% (95% confidence intervals ⫽ 6.4% to 9.0%), without a trend toward improvement in survival. Over the past 5 years, new and more effective treatments have been developed based on an increased understanding of the biology of this form of prostate cancer. The therapeutic targets that have emerged include the proteins that both negatively and positively modulate apoptosis, cytoplasmic microtubules, the nuclear matrix, peptide growth factors, and topoisomerases. The recent approval of the mitoxantrone/prednisone combination for the palliation of bone pain in patients with hormone refractory prostate cancer has helped dispel the concept that chemotherapy is ineffective. Along with other new and promising agents and therapies, oncologists have more options for treating hormone refractory prostate cancer, which, at the very least, can improve quality of life and may even prove to prolong survival. This article will review some of these treatment combinations. 0090-4295/99/$20.00 PII S0090-4295(99)00452-5
MECHANISMS OF CHEMOTHERAPEUTIC CELL DEATH Classic drug resistance mechanisms (e.g., multidrug resistance through p-glycoprotein, as well as alterations of the enzyme pathways responsible for antimetabolite activity) are only partially responsible for the ineffectiveness of some chemotherapeutic agents. Recent studies in the mechanism of anticancer drug action have focused on the proteins that regulate apoptosis or programmed cell death, which can be induced by growth factor deprivation, glucocorticoids, and chemotherapy. New treatments are now being designed with both resistance and apoptotic pathways in mind. In designing rational combinations, the oncologist should now account for complementary cell death mechanisms and potential resistance mechanisms. Several different pro- and anti-apoptotic pathways exist and have been identified in androgen-independent prostate cancer cell lines and tissues. The antiapoptotic protein bcl-2 is expressed in approximately 65% of androgen-independent human prostate cancer specimens.3 Transfection of bcl-2 into the human prostate cancer cell line LNCaP imparts resistance to androgen deprivation.4 Bcl-2 transfection into the Dunning-G rat prostate cancer cell line will significantly decrease the cytotoxic effect of doxorubicin when compared with nontransfected lines.5 Thus, bcl-2 may impart both androgen-independent growth as well as chemoresistance. Chemotherapeutic agents, which inactivate bcl-2 by phosphorylation, include those that stabilize and destabilize tubulin, such as the taxanes and vinca alkaloids. The Fas (AP0-1, CD95) ligand, the target of which is a cell surface protein receptor, is expressed in human prostate cancer cell lines that are sensitive to anti-Fas mediated cytotoxic apoptosis.6 Modulation of these pathways may overcome an apoptotic block rendered by mutant p53, which as wild type is necessary for some forms of chemotherapy-induced apoptosis. Mutant p53 is expressed in approximately 80% of human androgenindependent prostate bone marrow metastates in patients who failed androgen ablation.7 RESPONSE ASSESSMENT Assessment of anticancer drug activity in patients with hormone refractory prostate cancer has presented a challenge to oncologists over the past 10 years. Because approximately 80% of patients have disease limited to bone, standard phase II criteria cannot be used for the measurement of response. Surrogate endpoints are currently used in the reporting of clinical trials. These include post therapy decreases in serum PSA, quality of life, and pain scales. A decrease in PSA appears to correlate with survival. UROLOGY 54 (Supplement 6A), December 1999
One of the most controversial surrogate markers is the decrease in serum PSA as a response parameter. Studies have indicated that decreases in this marker can be prognostic. A mulitvariate analysis by Kelly et al.,8 of 110 patients treated in seven consecutive hormone refractory prostate cancer clinical trials at Memorial Sloan Kettering Cancer Center, demonstrated that PSA decreases of ⱖ 50% and a decrease in the natural log of lactic dehydrogenase (LDH) were the most important prognostic factors for survival. A second analysis by Smith et al.9 found that a PSA ⱖ 50% 8 weeks post-treatment in patients treated with estramustine and etoposide was predictive of prolonged survival. Caution must be exercised when interpreting PSA data, as some chemotherapeutic agents may modulate PSA expression.10 Suramin, the putative growth factor antagonist, has been demonstrated to decrease expression of PSA messenger RNA without causing cell death. Retinoids may actually increase PSA expression and, thus, can mislead the investigator to believe that a drug is inactive in a patient. Although PSA can serve as a preliminary screen for drug activity, the efficacy of chemotherapeutic drugs must ultimately be assessed in randomized phase III trials. MITOXANTRONE-BASED REGIMENS Initial phase II studies using mitoxantrone, a topoisomerase II inhibitor, and 10 mg prednisone given orally twice a day demonstrated that 36% of the men treated had a palliative response; 1 of 7 patients with measurable disease evidenced a partial response.11 Two randomized trials have demonstrated the superiority of this combination over corticosteroid therapy in alleviating bone pain. Tannock et al. randomized 161 men with hormone refractory prostate cancer to receive either one dose of 10 mg prednisone, or 12 mg/m2 mitoxantrone every 3 weeks combined with prednisone. A significant improvement in palliation of bone pain (29% vs. 10%, P ⫽ 0.011) was observed in patients who received the combination when compared with those who only received prednisone. The duration of this pain response in patients treated with the combination was also significantly longer (43 vs. 18 weeks, P ⬍ 0.0001). Of the 50 patients who initially received prednisone and failed, 22% responded, as evidenced by improvement of bone pain, to the addition of mitoxantrone. This cross-over design precluded the detection of a survival difference.12 A Cancer and Leukemia Group B (CALGB) study compared the combination of 40 mg hydrocortisone with 14 mg/m2 mitoxantrone every 3 weeks to 40 mg cortisone. The entry criteria and endpoints for this trial differed significantly from those of the Canadian study; asymptomatic patients were eligi31
ble. The primary endpoint of this trial was survival, with palliation of bone pain included in the secondary endpoints. No difference in survival was seen between the two arms, with patients surviving a median of 12.6 and 12.3 months for hydrocortisone and the combination of mitoxantrone and hydrocortisone, respectively. Time to treatment failure and disease progression were improved by 1.4 months when patients were treated with mitoxantrone combined with hydrocortisone. Quality of life indexes were better in the combination therapy arm, particularly for pain control.13 Based on the data from these two phase III studies, mitoxantrone was approved by the Food and Drug Administration for palliation of symptomatic bone pain in men with hormone refractory prostate cancer. ESTRAMUSTINE-BASED REGIMENS Estramustine, a combination of an estrogen with a nor-nitrogen mustard, disrupts cytoplasmic microtubules, inhibits assembly of the nuclear matrix, and inhibits the multidrug resistance transporter p-glycoprotein.14 The combination of estramustine with vinblastine,15–17 or VP-16,18 is commonly used in clinical practice with both regimens demonstrating a decrease in PSA of ⱖ50% in 45% to 52% of patients, and objective responses in 26% to 33% of patients (Table I). A recent study randomized 201 patients to receive either the combination of 600 mg/m2 estramustine given orally plus 4 mg/m2 vinblastine given intravenously once a week for 6 weeks or 4 mg/m2 vinblastine alone given intravenously for 6 weeks. Treatment in each arm was repeated after a 2-week break. The results demonstrated a trend toward improved survival in the estramustine/vinblastine arm (11.9 vs 9.2 months for vinblastine alone) and a small, yet statistically significant, improvement in time to progression for the combination therapy arm. Estramustine may provide myeloprotection; those patients who received the combination of estramustine plus vinblastine had a significantly lower rate of granulocytopenia (grades 2, 3, and 4 ⫽ 7%, 7%, and 1%) when compared with those who received vinblastine alone (grades 2, 3, and 4 ⫽ 27%, 18%, and 9%).19 TAXANE-BASED THERAPY Taxanes, either as single agents or combined with estramustine, have been evaluated extensively in hormone refractory prostate cancer. Differences in chemical structure may account for different sites of action of the taxanes. Preclinical studies demonstrate that docetaxel and paclitaxel bind to different sites on B tubulin (Tau vs. Nterminal), affect different mitotic structures (cen32
trosome vs. mitotic spindle), and arrest cells at different phases of the cell cycle (S vs. G2M).20 Although the mechanism of the antitumor activity of the taxanes is postulated to be a result of the inhibition of depolymerization of microtubules, recent data also demonstrate that both docetaxel and paclitaxel inhibit the anti-apoptotic effect of bcl-2. In vitro, docetaxel is approximately 100-fold more effective in phosphorylating bcl-2 than paclitaxel.21 This may account for the observed differences in clinical activity between these drugs as single agents in men with hormone refractory prostate cancer. Initial studies using paclitaxel, as a single agent at doses of 130 mg/m2 to 170 mg/m2 by continuous infusion over 24 hours, demonstrated a partial response rate of 4.3%, with one patient having a ⬎75% decrease in PSA.22 In contrast, when patients are treated with 75 mg/m2 docetaxel every 3 weeks, 62% of patients demonstrated a greater than 50% decrease in PSA, with 28% having a partial response in soft tissue metastases.23 However, one cannot make any definite conclusions about the efficacy of a particular taxane based on these small Phase II studies. When estramustine is combined with either paclitaxel or docetaxel in vitro, greater than additive cytotoxicity is noted.24 Hudes et al.25 evaluated the combination of 120 mg/m2 estramustine plus paclitaxel by continuous infusion over 96 hours in 33 evaluable hormone refractory prostate cancer patients and found that 52% of patients treated had a ⬎50% PSA decline. Objective responses were observed in 44% of patients with measurable soft tissue lesions. The median survival reported in this study was 17 months. This regimen was well tolerated, with the most common grade 3 or 4 side effects being leukopenia (21.2%) and anemia (18.1%). Grade 3 or 4 toxicities attributed to estramustine included edema (15.2%), nausea (6.1%), and vascular events (6.1%). In a phase I study, Petrylak et al.26 combined 280 mg estramustine three times a day for the first 5 days with 40 mg/m2 to 80 mg/m2 docetaxel (day 2) every 21 days in 34 men with hormone refractory prostate cancer. Overall, 62% of patients treated with docetaxel had a ⱖ50% PSA decrease; objective responses were observed in 28% of patients (Table II). Of 15 patients with symptomatic bone pain requiring narcotic analgesia, 53% discontinued all pain medications for a median of 6 weeks. Neutropenia was dose-limiting at 80 mg/m2. The recommended phase II dose of estramustine and docetaxel was 70 mg/m2 in minimally pretreated patients (MPT) (minimal pretreatment: ⱕ2 prior chemotherapies, ⱕ2 prior radiation therapies, no history of radioisotope therapy, no evidence of superscan on bone scan, and no history of whole pelvic radiation therUROLOGY 54 (Supplement 6A), December 1999
TABLE I. Estramustine-based chemotherapy trials in androgenindependent prostate cancer Drug/Combination Estramustine Estramustine Estramustine Estramustine
⫹ ⫹ ⫹ ⫹
vinblastine etoposide paclitaxel docetaxel
N
PSA Decrease >50%
Objective Response
83 42 34 34
45% 52% 52% 62%
26% 33% 44% 28%
PSA ⫽ prostate-specific antigen.
TABLE II. Docetaxel ⴙ estramustine: phase I studies PSA Study Petrylak et al.26 MPT EPT Kreis et al.27 Natale et al.32 (E ⫹ T)
Patients
>50%
>75%
20 12 17 13
70% 50% 82% 77%
40% 8% 67% 46%
Objective Response*
Symptomatic Improvement
Median Survival
28%
53%
24 mo
NR 60%
NR 77%
NR NR
Recommended Phase II Regimen (mg/m2) T T T T
70 60 70 35
3 3 3 1
times/week; E 280 times/wk; E 280 times/wk; E 12/kg/day time/wk; E 280–420
E ⫽ estramustine; EPT ⫽ extensively pretreated patients; MPT ⫽ minimally pretreated patients; NR ⫽ no response; PSA ⫽ prostate-specific antigen; T ⫽ docetaxel.
apy), and 60 mg/m2 in patients who had extensive prior therapy (EPT) (extensively pretreated patients who did not fit the MPT category). A second phase I study by Kreis et al.27 evaluated the combination of 14 mg/kg/day estramustine continuously with 40 mg/m2 to 70 mg/m2 docetaxel. Neutropenia was dose-limiting at 80 mg/ m2. In 17 patients treated at dosages ranging from 40 mg/m2 to 70 mg/m2, 82% of patients achieved a ⬎50% decrease in PSA. Phase II studies have confirmed this initial PSA decrease rate. In a study designed to evaluate the independent response rate of 60 mg dexamethaseone given orally every 3 weeks, 0 of 12 patients had a 50% PSA decrease, whereas 11 of 12 patients treated with 70 mg/m2 estramustine had a ⬎50% PSA decrease; 3 of 4 patients had a partial response in soft tissue.28 Savarese et al.29 evaluated 10 mg/kg estramustine given in the first 5 days with 70 mg/m2 docetaxel and 40 mg hydrocortisone given once orally in 40 men with hormone refractory prostate cancer. Of 9 patients with soft-tissue metastases, 4 had a partial response. A ⬎50% PSA decrease was observed in 11 of 19 evaluable patients. Although neutropenia appears to be the most common side effect with this combination, the most serious side effects of venous or arterial vascular events occurred in 10% of patients treated with the estramustine/docetaxel combination. It may be possible to reduce the rate of thromboembolic events by either reducing the estramustine dose or adding prophylactic anticoagulants. UROLOGY 54 (Supplement 6A), December 1999
Taxanes, administered weekly, are also being evaluated in men with hormone refractory prostate cancer.30 Using a continuous oral dosage of 600 mg/m2/day estramustine starting 24 hours before paclitaxel and 60 mg/m2 to 118 mg/m2 paclitaxel every week, Haas et al.31 found the dosage of estramustine had to be reduced to 280 mg twice a day because of nausea or thromboembolism. Six of 11 patients with measurable disease had a partial response, whereas 9 of 14 patients had a ⬎50% PSA decrease. Natale and Zaretsky32 studied 20 mg/m2 to 40 mg/m2 docetaxel given weekly with 420 mg estramustine administered for 3 or 4 days. Deep venous thrombosis or grade 3/4 neutropenia was observed in 2 and 4 patients, respectively. Of the 18 patients entered, 78% and 67% of patients had a ⬎50% PSA decrease or objective response, respectively. PHASE III SOUTHWEST ONCOLOGY GROUP STUDY In 1999, patients with hormone refractory prostate cancer are being treated earlier; in fact, a greater proportion of men are classified as hormone refractory based solely on an increasing PSA, without progression by bone scan or computerized tomography. Although the reported estramustine/ docetaxel studies required patients to have radiographic evidence for metastases, it is possible that increases in survival could be related to patient selection or a statistical variance based on the small numbers of patients treated. Only a randomized 33
TABLE III. Southwest Oncology Group (SWOG) 9916: A randomized phase III study of docetaxel ⴙ estramustine versus mitoxantrone ⴙ prednisone in patients with hormone refractory prostate cancer* Hormone Refractory Advanced Prostate Cancer
R A ------⬎ N D O M I Z ------⬎ E
Docetaxel 60 mg/m2 day 2† ⫹ estramustine 280 mg tid days 1–5 q3 wk
Mitoxantrone‡ 12 mg/m2 day 1 ⫹ prednisone 5 mg bid days 1–21 q3 wk
* 620 patients to be entered to detect a 33% survival difference. † Escalated to 70 mg/m2 if no grade 3 or 4 toxicities are observed in cycle 1. Dexamethasone was given at midnight, 6 AM, and just prior to docetaxel administration. ‡ Escalated to 14 mg/m2 if no grade 3 or 4 toxicities are observed in cycle 1.
study would definitively answer the question of whether estramustine/docetaxel truly improves survival in this patient population. In 1999, a phase III study will begin in the Southwest Oncology Group to evaluate survival in patients with metastatic hormone refractory prostate cancer (Table III). The control arm is 12 mg/m2 mitoxantrone (escalated to 14 mg/m2 if no grade 3 or 4 toxicities are observed in cycle 1) combined with 5 mg prednisone given orally twice a day, days 1–21 q3 weeks. In arm 2, patients will be treated with 280 mg estramustine given orally three times a day for days 1 to 5, 60 mg/m2 docetaxel on day 2 (escalated to 70 mg/m2 if no grade 3 or 4 toxicities are observed in cycle 1), and 20 mg dexamethasone given at midnight, 6 AM, and just before docetaxel administration. The trial is designed to detect a 33% difference in survival between the two arms at a power of 80%. Secondary endpoints include quality of life, response in measurable disease, and improvement of bone pain. The trial will accrue 620 patients over a 3-year period. CONCLUSION To date, no single agent or combination therapy has proven to prolong survival in patients with metastatic hormone-refractory prostate cancer. Taxanes, administered singly or in combination with estramustine, have demonstrated activity in early phase I/II studies in patients with hormone refractory prostate cancer. A trend toward improved survival has been observed in phase I studies combining estramustine and docetaxel, as well as in phase II studies of estramustine and paclitaxel. These results in small cohorts of patients have provided impetus for future randomized studies. Only randomized trials can confirm whether these survival trends can be confirmed or were the result of patient selection or statistical 34
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